Telomerase activity has been found in 85-95 percent of all primary tumors that have been assayed, but not in somatic cells with the exception of germ cells and proliferative cells of renewal tissues (which express low levels). The connection between telomerase and cancer has led to the hypothesis that telomerase activity is necessary for sustained proliferation of most cancer cells, and that telomerase inhibitors might be effective chemotherapeutic agents. The objective of this proposal is the development of telomerase inhibitors as tools to validate the connection between telomerase and cancer. Such inhibitors would be lead compounds for the design of anti-telomerase therapeutics and further the understanding of the interplay between telomerase and other cellular proteins. Specific aims of this proposal include the discovery and optimization of new inhibitor chemistries in vitro, the use of inhibitors as structural and functional probes for telomerase, and the use of the inhibition of telomerase activity to help resolve whether telomerase activity is necessary for cell immortality.